tbuckley/cabot-search huggingface dataset:
Abstract 972: MMR-deficiency is the most prominent genetic feature of prostate cancer metastases organotropism
Authors: Daniel Vis, Sander Palit, Marie Corradi, Martijn Lolkema, Niven Mehra, Edwin Cuppen, Lodewyk FA Wessels, Rene Bernards, Wilbert Zwart, Michiel S. van der Heijden, Andries M. Bergman
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) is the most prevalent, non-cutaneous, cancer in men in the Western world. Disease confined to the prostate can be cured, but metastatic disease cannot. PCa metastases are found in bone, lymph-nodes, liver and other visceral organs (visceral), in decreasing order of frequency. After an initial response to androgen receptor directed therapy, metastatic disease will inevitably recur as metastatic castration resistant prostate cancer (mCRPC), which is hallmarked by high morbidity and mortality. Since it is previously established, that the site of metastasis correlates with prostate cancer survival, we need a better understanding of metastatic organotropism. Therefore, we took advantage of the largest Whole Genome Sequencing (HiSeq X Ten system using the paired-end sequencing protocol) data set of mCRPC metastases to date. Molecular profiling of 326 metastases (Bone: 105, Lymph-node: 149, Liver: 49, Visceral: 23) revealed genetic determinants associated with organ-specific metastasis. First, we assessed differential occurrence of mutations in genes associated with targetable pathways. RB1 alteration were enriched in liver (35%) and in visceral metastases (30%), while lower rates were found in bone (10%) and lymph-nodes (13%)(Fisher exact test, p: 0.012). Analysis of aggregated pathway alteration data revealed a trend for increased frequency of alterations in the DNA repair and PI3K pathways in lymph node vs. bone metastases (p: 0.066 and 0.066, respectively). Next, we explored differential tumor mutational burden (TMB) between the sites. A higher TMB was observed in liver and visceral metastases compared to bone and lymph node metastases, while there was no difference between liver and visceral. The increased TMB in liver and visceral samples was associated with an MMR-deficiency mutational signature. Alterations in MSH6, MLH1 and POLD3 characterized a significant proportion of high TMB liver metastases, whereas high TMB visceral metastases predominantly showed MSH2 and POLD1 alterations.In conclusion: Our findings implicate high TMB/MMR-deficiency is a characteristic feature of liver and visceral PCa metastases, potentially impacting disease progression. Moreover, since response to immune check-point inhibitors is associated with high TMB, our findings might direct choice of therapy. Citation Format: Daniel Vis, Sander Palit, Marie Corradi, Martijn Lolkema, Niven Mehra, Edwin Cuppen, Lodewyk FA Wessels, Rene Bernards, Wilbert Zwart, Michiel S. van der Heijden, Andries M. Bergman. MMR-deficiency is the most prominent genetic feature of prostate cancer metastases organotropism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 972.
Abstract 5392: Magnolol induces apoptosis and inhibits invasion ability via suppression of STAT3 signaling in glioblastoma multiforme cells
Authors: Sin-Rong Lee, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu
Journal: Cancer Research (2022)

Abstract Magnolol is a phenolic compound extracted from magnolia officinalis, exhibited anti-tumor potential against many types of cancers. Magnolol has also recognized as an anti-inflammation agent which can downregulate several inflammation signals transduction. Glioblastoma multiforme (GBM) is the most common central nervous system (CNS) tumor and associated with poor prognosis among adults due to rapid growth and aggressive invasion. However, the treatment efficacy of current standard therapy for GBM is remaining unsatisfied. Nevertheless, whether magnolol may suppress GBM progression and its underlying mechanism has not been elucidated. Thus, the purpose of this study was to investigate the mechanism and therapeutic efficacy of magnolol on GBM.First of all, we validated the potential treatment targets of GBM with the GEPIA (Gene Expression Profiling Interactive Analysis) analysis and Western blotting assay. GEPIA data indicated the PKCδ/STAT3 signaling pathway as a potential target of GBM that may affect patient survival. In our results, magnolol can effectively suppress the phosphorylation and the nuclear translocation of STAT3 in GBM cells. Then, we used the MTT assay to investigate the cytotoxicity of GBM cells after various dose of magnolol treatment. We also detected the extrinsic/intrinsic apoptosis induction ability of magnolol on GBM cells. This study also demonstrated that magnolol may significantly trigger the loss of mitochondrial membrane potential, and the activation of cleaved caspase-3, -8 and -9. Transwell invasion and wound healing assays was used to identify the suppression of migration and invasion effects of magnolol on glioblastoma cells. Meanwhile, tumor invasion and migration ability and the associated genes, including MMP9 and uPA, were all diminished by magnolol treatment. In sum, our results demonstrated that magnolol suppressed GBM progression may be associated with the inactivation of PKCδ/STAT3 signaling transduction. Citation Format: Sin-Rong Lee, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Magnolol induces apoptosis and inhibits invasion ability via suppression of STAT3 signaling in glioblastoma multiforme cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5392.
Abstract 615A: HuGEMM࣪ modelling toxicology of species-specific immune checkpoint inhibitors
Authors: Daniel XF He
Journal: Cancer Research (2022)

Abstract Background: Immune checkpoint inhibitors, including anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have led to impressive clinical outcomes in treating certain cancers. However, the overall success rate of immunotherapeutic drugs remains low, due to poor efficacy (cancer immunotherapeutic effect [CITE]) or unexpected safety risks such as immune-related adverse events (irAEs), underlining the importance of predictive preclinical animal models. Notably, most immunotherapies cannot be modeled in xenograft tumor models, due to their immunodeficient phenotype, or syngeneic models, as most biologics are usually species-specific. Given these limitations, genetically engineered humanized mouse models (HuGEMM࣪) and syngeneic cell lines (HuCELL࣪), where human drug target gene(s) replace the original mouse ortholog(s), have been broadly used to assess species-restricted biologics for CITE. Since most irAEs in biologics are on-target toxicities, it is potentially possible to model the irAEs of biologics using non-tumor bearing HuGEMMs. In this study, the PD-1/CTLA-4 double knock-in (dKI) HuGEMM is used as an example to provide more insights into irAE evaluation in preclinical models. Methods: The PD-1 and CTLA-4 HuGEMM in BALB/c backgrounds were developed by substituting the mouse extracellular domains with their human counterparts, followed by crossbreeding to create dKI mice for both targets. The juvenile dKI mice (age 4-5 weeks) were treated with the vehicle control, anti-human PD-1, and a combination therapy of anti-human PD-1/anti-human CTLA-4. The models were monitored for toxicity parameters, including general welfare, body weight, mortality, gross pathology (arthritis, skin inflammation, and colitis scoring), and histopathology of different organs at study termination. Results: No body weight loss was observed throughout the study in all treatment groups. No mortality was observed in models treated with a monotherapy, while in the combination group (anti-human PD-1/anti-human CTLA-4), five mice displayed lethargy and tachypnea symptoms, and four mice experienced severe adverse effects. Per gross pathology analysis, combination treatment caused significant arthritis in the feet of the mice at study end. Histopathology analysis of the combination treatment group samples demonstrated colon epithelia damage and heart lymphocyte infiltration at termination. These observations for toxicity or irAE profiles are in line with those observed in patients undergoing the same treatment regimen. Conclusions: HuGEMM engineered to express human targets could be used in preclinical studies to test for assessing irAE of biologics. Citation Format: Daniel XF He. HuGEMM࣪ modelling toxicology of species-specific immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 615A.
Abstract 1977: Extending the capabilities of a high-parameter immunophenotyping assay with cytoplasmic staining applications for mass cytometry
Authors: Noah Saederup, Huihui Yao, Michael Cohen, Leslie Fung
Journal: Cancer Research (2022)

Abstract Mass cytometry, empowered by CyTOF® technology, utilizes monoisotopic metal-tagged antibodies and a high-sensitivity mass cytometer to allow high-dimensional single-cell analysis in complex biological samples. The 30-marker panel Maxpar® Direct™ Immune Profiling Assay™ (Cat. No. 201325) for suspension mass cytometry provides an unprecedented sample-to-answer solution for detecting and analyzing 30 surface markers in a single experiment. With 18 open mass channels for additional biological markers, the Maxpar Direct Assay facilitates panel expansion and enables flexibility for higher multiplexity and applications. Among the potential complementary applications with the Maxpar Direct Assay, intracellular cytokine staining (ICS) is of particular interest as it may be used to assess infiltrating immune cell phenotypes in the tumor microenvironment. However, for the purpose of assessing cell viability in this workflow, the effectiveness of the Cell-ID™ Intercalator-Rh (Cat. No. 201103) that is included in the Maxpar Direct Assay is in question, since cell permeabilization during ICS can potentially damage the DNA-intercalator bondIn this study, we investigated the compatibility of the Cell-ID Intercalator-Rh (103Rh) with intracellular staining. To do this, we stained either human peripheral blood mononuclear cell (PBMC) or whole blood samples (FLDM-400287) with the Maxpar Direct Assay followed by intracellular staining for the detection of expressed cytokines. The intercalator was evaluated for its ability to discriminate live and dead cells when the sample undergoes surface antibody staining. The monoisotopic Cell-ID Cisplatin-194Pt (Cat. No. 201194) was used as the control to provide benchmark measurement of cell viability of the samples. For both sample types, known percentages of heat-killed PBMC were spiked into the samples in order to evaluate the influence of dead cells. We demonstrate that 103Rh provides equivalent functionality as a cell viability indicator during intracellular staining for cytoplasmic proteins compared to Cell-ID Cisplatin-194Pt. This work was designed to support the use of the Maxpar Direct Immune Profiling Assay in combination with additional intracellular markers. Overall, these findings expand the applicability of Cell-ID Intercalator-Rh (103Rh) to processes that involve cytoplasmic staining. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Noah Saederup, Huihui Yao, Michael Cohen, Leslie Fung. Extending the capabilities of a high-parameter immunophenotyping assay with cytoplasmic staining applications for mass cytometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1977.
Highlights from this issue
Authors: The Triumvirate
Journal: Thorax (2022)

1. Methods are described for the determination of acetophenetidin and p-phenetidin in biological fluids and tissues. 2. The route of metabolism of acetophenetidin in man is as follows: the major fraction of the drug is rapidly deethylated to N-acetyl p-aminophenol; this compound is excreted in a conjugated form; a minor fraction deacetylates to form p-phenetidin; this compound was shown to be the precursor of the substance which oxidizes hemoglobin to methemoglobin. The analgesic and antipyretic action of acetophenetidin is exerted mainly through N-acetyl p-aminophenol which is an active analgesic and antipyretic.
Abstract 5088: Identification of <i>NOTCH</i> mutation as novel predictor to efficacious immunotherapy in colorectal cancer
Authors: Xiaoyang Xia, DongShan You, Jing Cao, JingHui Huang, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai
Journal: Cancer Research (2022)

Abstract Background: NOTCH, as an oncogene, has been shown to be closely associated with radiation and chemotherapy, hormone therapy, and other molecular targeted therapies (such as anti-EGFR and anti-PI3K molecular targeted therapies) in a variety of tumors, and even in drug resistance mechanisms. However, the correlation between NOTCH mutations and immunotherapy in colorectal cancer (CRC) has not been reported. Methods: We retrospectively identified NOTCH mutation and treatment outcomes. The relationship between clinical pathologic features and NOTCH were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. Results: We retrospectively analyzed 108 CRC patients who received immunotherapy, including 31 patients with NOTCH mutation (MUT) and 78 patients with NOTCH wide-type (WT). NOTCH mutation was discovered to be enriched in MSI instable and associated with significant better overall survival (HR, 0.4; 95% CI, 018-0.9; P=0.0272). Although compared with NOTCH WT, no association was observed between NOTCH1/2/4 MUT and overall survival, Kaplan-Meier survival analysis showed that patients with NOTCH3 MUT obtained better OS (not reach vs. 14 months, HR, 0.17; 95% CI 0.04-0.74; P=0.0176). In addition, in an in-house Chinese CRC cohort (n=1968), we found 322 (16.4%) patients with NOTCH mutations, including NOTCH1/2/3/4 mutation frequency were 43.5%, 32.9%, 46.9% and 12.1%, respectively. 206 (60.4%) patients had one NOTCH mutation, and only 20 (6.2%) patients had more than four mutations. NOTCH mutations were significantly associated with higher TMB levels (P&amp;lt;0.0001) and PD-L1 positive (P=0.0011) in the in-house Chinese CRC cohorts. Conclusions: Our results suggest that NOTCH1/2/3/4 mutation may be a potential predictor to favorable ICI response in CRC patients. The exact mechanisms underlying NOTCH mutations are needed to be further evaluated. Citation Format: Xiaoyang Xia, DongShan You, Jing Cao, JingHui Huang, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. Identification of NOTCH mutation as novel predictor to efficacious immunotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5088.
Abstract 3379: Multi-cohort study shows HCC is associated with a relative regional reduction in TGFBR2 in liver biopsies from patients with cirrhosis
Authors: Krishanu Bhowmick, Richard Amdur, Xiyan Xiang, Herbert Yu, Linda L. Wong, Shuyun Rao, Aiwu R. He, Karan Amin, Daewa Zaheer, Raj K. Narayan, Sanjaya K. Satapathy, Chandan Guha, Patricia S. Latham, Kirti Shetty, Nancy R. Gough, Lopa Mishra
Journal: Cancer Research (2022)

Abstract Background: Early detection of hepatocellular carcinoma (HCC) is challenging partly because most patients also have cirrhosis. Furthermore, patients with cirrhosis are at high risk of developing HCC. Loss of function of the transforming growth factor β (TGF-β) pathway is associated with HCC. The goal of this study was to determine if a reduction in TGF-β receptors (TGFBR1, TGFBR2) was able to reliably and reproducibly predict HCC in cirrhotic tissue. Methods: We performed quantitative immunohistochemical (IHC) analysis of biopsy tissue from patients with cirrhosis with or without HCC using 3 separate sets of samples. We developed an automated image analysis pipeline to quantify IHC of TGFBR1 and TGFRB2 in liver biopsies. Using logistic regression modeling, we evaluated the predictive power of staining intensity of TGFBR1, TGFBR2, or the combination in differentiating HCC from cirrhosis. Results: We found a consistently significant reduction in TGFBR2 in HCC (p &amp;lt; 0.02) among independent patient cohorts from 3 separate institutions. With the data, we developed an artificial intelligence-based image analysis pipeline that confirmed the significant reduction in TGFBR2 staining intensity in HCC compared to cirrhotic tissue (p &amp;lt; 0.002). Unfortunately, logistic regression modeling of the quantitative data showed that there is not a simple threshold of TGFBR2 staining intensity that is diagnostic of HCC. Instead, in 84% of samples with HCC, HCC was associated with a relative regional reduction in TGFBR2 compared to tumor-adjacent cirrhotic tissue. Conclusions: The qualitative and quantitative analyses indicate that evaluating biopsy samples for a reduction in TGFBR2 abundance relative to the surrounding cirrhotic tissue could be an early indicator of the development of HCC in high-risk groups undergoing surveillance for HCC. Furthermore, an automated image analysis pipeline for quantitative IHC of TGFBR staining could improve the reliability of image analysis across institutions participating in clinical trials. Citation Format: Krishanu Bhowmick, Richard Amdur, Xiyan Xiang, Herbert Yu, Linda L. Wong, Shuyun Rao, Aiwu R. He, Karan Amin, Daewa Zaheer, Raj K. Narayan, Sanjaya K. Satapathy, Chandan Guha, Patricia S. Latham, Kirti Shetty, Nancy R. Gough, Lopa Mishra. Multi-cohort study shows HCC is associated with a relative regional reduction in TGFBR2 in liver biopsies from patients with cirrhosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3379.
Abstract 6248: Modulation of CD22 protein expression in childhood leukemia by pervasive splicing aberrations: Implications for CD22-directed immunotherapies
Authors: Sisi Zheng, Elisabeth Gillespie, Ammar S. Naqvi, Katharina E. Hayer, Zhiwei Ang, Manuel Torres-Diz, Mathieu Quesnel-Vallières, David A. Hottman, Asen Bagashev, John A. Chukinas, Carolin Schmidt, Mukta Mukta Asnani, Rawan Shraim, Deanne M. Taylor, Susan R. Rheingold, Maureen M. O’Brien, Nathan Singh, Kristen W. Lynch, Marco Ruella, Yoseph Barash, Sarah K. Tasian, Andrei Thomas-Tikhonenko
Journal: Cancer Research (2022)

Abstract Downregulation of surface epitopes causes post-immunotherapy relapses in B-lymphoblastic leukemia (B-ALL). Here we demonstrate that mRNA encoding CD22 undergoes aberrant splicing in B-ALL. We describe the plasma-membrane-bound CD22 Δex5-6 splice isoform resistant to CAR-T cells targeting the third immunoglobulin-like domain of CD22. We also describe splice variants skipping the AUG-containing exon 2 and failing to produce any identifiable protein; therefore, this event is rate-limiting for epitope presentation. Indeed, forcing exon 2 skipping with Morpholino oligonucleotides reduced CD22 protein expression and conferred resistance to the CD22-directed antibody-drug conjugate inotuzumab in vitro. Furthermore, among inotuzumab-treated pediatric B-ALL patients, we identified one non-responder in whose blasts Δex2 isoforms comprised the majority of CD22 transcripts. In a second patient, a sharp reduction in CD22 protein levels during relapse was driven entirely by increased CD22 exon 2 skipping. Thus, dysregulated CD22 splicing is a major mechanism of epitope downregulation and ensuing resistance to immunotherapy. Citation Format: Sisi Zheng, Elisabeth Gillespie, Ammar S. Naqvi, Katharina E. Hayer, Zhiwei Ang, Manuel Torres-Diz, Mathieu Quesnel-Vallières, David A. Hottman, Asen Bagashev, John A. Chukinas, Carolin Schmidt, Mukta Mukta Asnani, Rawan Shraim, Deanne M. Taylor, Susan R. Rheingold, Maureen M. O’Brien, Nathan Singh, Kristen W. Lynch, Marco Ruella, Yoseph Barash, Sarah K. Tasian, Andrei Thomas-Tikhonenko. Modulation of CD22 protein expression in childhood leukemia by pervasive splicing aberrations: Implications for CD22-directed immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6248.
Aiming for the Cure in <i>ERBB2</i>-Positive Metastatic Breast Cancer—Should We Go “All In”?—Reply
Authors: Paolo Tarantino, Heather A. Parsons, Sara M. Tolaney
Journal: JAMA Oncology (2022)

In Reply We read with keen interest the comments from Drs Rala de Paula and Crocamo on our Review discussing strategies to improve long-term outcomes for ERBB2-positive metastatic breast cancer (MBC).1
Abstract 1788: Engineered destabilized AU rich elements on the 3UTR of HER2 degrades HER2, inhibits proliferation, and induces apoptosis in HER2 positive trastuzumab resistant breast cancer cells
Authors: Chidiebere U. Awah, Fu Dong, Fayola Levine, Leonard Ash, Yana Glemaud, Olorunseun Ogunwobi
Journal: Cancer Research (2022)

Abstract Resistance to molecular targeted therapy is a major challenge facing breast cancer patients and unfavorably impacts clinical outcomes, leading to hundreds of thousands of deaths yearly. Resistance to cancer therapies arises from many factors. One of the key factors driving resistance is oncogenes which initiate pro-growth, pro-survival and metastatic programs that enable cancers escape various therapies. In HER2+ breast cancer, the oncogene HER2 is the master driver of this tumor. Trastuzumab effectively targets HER2. While this is generally successful, some patients who have HER2+ breast cancer develop resistance to trastuzumab and there are limited treatment options for them. Moreover, for low HER2+ expressing breast cancer, there are limited treatment options for them. And in African American women who have HER2+ breast cancer, there is disparity in their treatment outcomes. We have discovered that 3’UTR of HER2 is enriched with poly U stabilizing AU rich elements (ARE). We have developed a novel technology wherein we engineered the stabilizing HER2 3’UTR ARE motifs to destabilizing motif in HER2+ and HER2+ trastuzumab resistant breast cancer cells to control HER2 transcript. We achieved complete degradation of HER2 within 4-8 days in HER2+ wildtype breast cancer cells and 9-11 days in HER2+ trastuzumab resistant breast cancer cells. We had loss of cancer cell viability by more than 90%. We also show that control of HER2 transcript downregulated HER2-dependent kinases, transcription factors, and HER2 interactome. Mechanistically, the control of HER2 transcript was achieved by destabilized ARE sequence specificity which triggered the proteins PARN, XRN1 and CNOT1 to degrade HER2 transcript and this led to induction of active caspase 3/7, reduction of cell size, and severe distortion and disruption of the cancer cell membrane leading to cell death. Taken together, we have a developed a novel approach to control HER2 transcript expression both on spatial and temporal scale. This novel approach offers applications for targeting HER2+ trastuzumab resistant breast cancer as well as other cancers resistant to HER2 targeted therapy and driven by pervasive oncogenic signals. Citation Format: Chidiebere U. Awah, Fu Dong, Fayola Levine, Leonard Ash, Yana Glemaud, Olorunseun Ogunwobi. Engineered destabilized AU rich elements on the 3UTR of HER2 degrades HER2, inhibits proliferation, and induces apoptosis in HER2 positive trastuzumab resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1788.